Method of stabilizing nialinamide against caking

ABSTRACT

A therapeutically active, tasteless niacinamide powder stable against caking during storage is described. Mixtures of fatty acid monoglycerides and diglycerides are used as the anti-caking component.

United States Patent De Ritter et al. 5] July 11, 1972 54] METHOD OF STABILIZING [56] References Cited NIALI AMIDE AINST AKI N AG C NG UNITED STATES PATENTS 2 t lm De tte l R [7 1 E s fi $32 git fl g g 3,080,292 3/1963 Koff ..424/38 Ni 3,080,293 3/1963 Koff ..424/266 3,308,217 3/1967 Lowy et a1. "424/266 [73] Assignee: Hoffman-La Roche Inc., Nutley, N]. e

Primary Examingr-Albert T. Meyers [22] Flled' Sept 1969 Assistant Examiner-Norman A. Drezin [2]] Appl.No.: 861,473 Anomey--Samuel I... Welt, Jon S. Saxe, Bernard S. Leon,

Gerald S. Rosen and R. Hain Swope Related US. Application Data [63] Continuation-impart of Ser. No. 596,768, Nov; 25, [571 ABSTRACT 1966- A therapeutically active, tasteless niacinamide powder stable against caking during storage is described. Mixtures of fatty [52] US. Cl ..424/266 acid monoglyceride-s and diglycerides am used as the i k [51] Int. Cl. ....A61k 15/12 ing componem [58] Field of Search ..424/38, 266

3 Claims, No Drawings METHOD OF STABILIZING NIALINAMIDE AGAINST CAKING RELATED APPLICATIONS This application is a continuation-in part of U. S. Pat. application Ser. No. 596,768 filed Nov. 25, 1966.

BRIEF SUMMARY OF THE INVENTION The invention relates to a method of producing a tasteless niacinamide-containing powder which is therapeutically active and stable against caking during storage.

BACKGROUND OF THE INVENTION The pharmaceutical use of niacinamide is well documented in the scientific literature. However, the inclusion of niacinamide in products designed for oral administration has caused substantial formulation problems. This is due to the fact that niacinamide has a highly disagreeable taste. To a great extent, the taste problem has been eliminated by coating niacinamide powder with a material which is substantially tasteless. In one prior art method, finely divided niacinamide is added to, and uniformly distributed throughout, a mixture of molten saturated fatty acids; the molten mixture is atomized into liquid droplets which are quickly chilled to form solid particles; and the solid particles are aged either prior or subsequent to dusting with silicic acid. The described procedure, which is disclosed in Koff U.S. Pat. No. 3,080,293 assigned to applicants assignee, has powder 50 the most successful method for producing palatable niacinamide-containing compositions. However, the palatable niacinamide-containing powder so produced has been found to cake during storage to the extent that, after 4 or weeks of storage, the powders form a solid mass which must be physically broken into pieces such as by the use of an instrument such as a metal bar.

This physical breaking up of the solid mass is necessary in order that the powder can be milled and blended. In accordance with the present invention, a tasteless therapeutically active niacinamide powder is formed which possesses im proved physical handling characteristics and which will not cake during storage.

DETAILED DESCRIPTION OF THE INVENTION In its broadest embodiment, the present invention is concerned with compositions which contain niacinamide as the active ingredient. In a more specific embodiment, the invention is concerned with improved niacinamide-containing compositions which are provided in the form of palatable powders, such powders being particularly characterized by their outstanding physical properties as manifested by a freedom from caking during storage.

It has been found that, in a process for producing palatable niacinamide-containing powders comprising the steps of (l) uniformly dispersing niacinamide-in a melted fatty material which is solid at normal room temperatures, (2) spraying the molten mixture into liquid droplets, (3) chilling the droplets to form solid particles and (4) aging said solid particles either before or after dusting same with silicic acid, compositions having improved physical characteristics and which are stable against caking during storage are obtained when there is used, as the fatty material in which niacinamide is dispersed, a mixture of monoglycerides and diglycerides of naturally occurring saturated fatty acids having a carbon chain length of from 16 to 18 carbon atoms.

The monoglyceride-diglyceride mixtures which are used in the practice of this invention are mixtures of glyceryl monostearate and glyceryl distearate containing substantial amounts of glyceryl monopalmitate and glyceryl dipalmitate. Products of this nature are commercially available. One such product, described as a granular food emulsifier,contains a mixture consisting essentially of monoand diglycerides of stearic and palmitic acids with no more than 0.01 percent butylated hydroxy anisole, 0.01 percent butylated hydroxy toluene and 0.0] percent citric acid added as preservatives. This product is commercially available under the tradename Atoms 150 from Atlas Powder Company, Wilmington, Del. Another commercial product containing suitable mixtures of monoglycerides and diglycerides of naturally occurring saturated fatty acids having from 16 to 18 carbon atoms is the product marketed under the tradename Hydrofol Glycerides T-57-L, by Archer-Daniels-Midland Co., Cleveland, Ohio. Either of these aforementioned products or any similar product can be employed in the practice of this invention.

The process by which the compositions of this invention are produced is known in the art. U.S. Pat. No. 3,080,292 in the name of Arnold Koff and also assigned to applicants assignee teaches the coating of riboflavin, thiamine and pyridoxine with the monoglyceride-diglyceride mixture utilized herein.

The teachings of this patent, however, offer no solution to the problem of caking during storage manifested by niacinamide coated in an analogous manner with stearic acid. The reason that the solution to the caking problem is not suggested by the teachings of U.S. Pat. No. 3,080,292 is that there is no parallel to be drawn between niacinamide and the vitamins coated therein in terms of storage stability. More specifically, riboflavin, thiamine and pyridoxine coated in the manner analogous to that of U.S. Pat. No. 3,080,293 with stearic acid will not form the solid mass during storage which is characteristic of stearic acid-coated niacinamide. Hence, it is surprising that applying the coating mixture described in U.S. Pat. No. 3,080,292 to niacinamide in a manner analogous to that described in U.S. Pat. No. 3,080,293 resolved the problem of caking during storage inherent in stearic acid-coated niacinamide.

In practicing the process of the present invention, the monoglyceride-diglyceride mixture is charged into a suitable vessel and it is heated to a temperature above its melting point. In the preferred embodiment of the invention, the glyceride mixture is heated to a temperature within the range of from about 65 to C. Thereafter, with the monoglyceride-diglyceride mixture being maintained continuously in a molten state, finely divided niacinamide is added to the melt and, by stirring, uniformly distributed throughout. In the next step of the preparative method, the molten mixture is transferred to a conventional spray-chilling tower or chamber wherein the molten material is atomized into liquid droplets which are allowed to fall, by gravity, to the bottom of the tower. Cool air, e.g., air cooled to a temperature of 20 C. or lower, is blown through the tower to quickly chill the droplets causing them to solidify or congeal. In a next step of the process, the product is collected in two high efficiency cyclone separators and screened in order to remove therefrom agglomerates or other coarse particles.

The nature of the device which is used to convert the molten mass into the desired liquid droplets does not limit the scope or the practice of the invention. In general, any conventional atomizing device such as a two-fluid nozzle or a high speed centrifugal atomizing wheel can be used. The only limitation on the device employed is that it is capable-of convetting the molten mass into liquid droplets which, when solidified, will provide a finished product the particles of which fall within the particle size range heretofore indicated.

After the formation of the niacinamide-containing powder in the manner described heretofore, the product is subjected to two further processing steps. One of these involves dusting the particles with silicic acid, the other involves aging the par- The quantity of silicic acid which is used for dusting purposes is not especially critical. ln general, a sufficient amount of silicic acid will be employed to impart satisfactory flowability characteristics to the product. Thus, for example, the products of this invention can be dusted with as little as about 0.5 percent by weight, based on the weight of the finished particles, and as much as about percent by weight, based on the weight of the finished particles, of silicic acid. Under ordinary circumstances, however, an amount of silicic acid equivalent to about 1.0 percent of the weight of the finished particles will be used. In the preferred embodiment of the invention, there will be employed the minimum amount of silicic acid needed to provide a product having the desired flow properties.

The aforementioned dusting step and the hereinafter described aging step are known per se. In the practice of the present invention they are carried out as described in the art. Aging serves to improve the taste of the particles. The duration of the aging period varies with the ambient conditions. ln general, the higher the temperature, the shorter the time required to obtain a completely palatable product. In carrying out the invention, one can determine, batch by batch, whether the product has been aged for a sufficiently long period. This is done simply by tasting a sample of the particles from each batch. When, in any instance, the bitter taste is no longer observed, the aging step, as to that batch, can be considered as complete. On the other hand, if upon testing a sample taken from a particular batch, the unpleasant taste persists, the batch must be aged for an additional period of time, i.e., until the disagreeable taste has disappeared. In one preferred method, the product is aged by keeping it in a drying oven, heated to a temperature of about 45 C., for a period of about 2 weeks. In an alternative preferred procedure, the particles are spread on trays and maintained in a dry atmosphere at about room temperature until the bitter taste characterizing the non-aged particles no longer persists.

As indicated heretofore, the quantity of silicic acid which is used in carrying out this invention is variable within rather wide limits. Similarly, the quantity of niacinamide and the quantity of monoglyceride-diglyceride mixture used is capable of wide variations. For example, niacinamide can comprise from about 24.5 percent to about 40 percent of the weight of the finished product. The monoglyceride-diglyceride mixture can comprise from about 59.0 percent to about 75 percent of the weight of the finished product. The products which are produced in the preferred embodiment, however, contain from about 32 percent to about 36 percent by weight of niacinamide, 67 percent to about 63 percent of the monoglyceride-diglyceride mixture and about 1.0 percent of silicic acid.

The products which are obtained in the practice of this invention are in the form of finely divided powders, the particles of which pass through a 30 mesh screen and up to about 50 percent by weight of which pass through a 200 mesh screen. These powders are completely palatable and they are freeflowing and non-agglomerating. They are suitable for use in any pharmaceutical application in which niacinamide or coated niacinamide products have previously been employed.

Samples of niacinamide were coated in the manner described above with stearic acid and with mixtures of glyceryl monostearate and glyceryl distearate containing substantial amounts of glyceryl monopalmitate and glyceryl dipalmitate, respectively. These samples were placed in lined, waterproof drums and aged at room temperature for a period of 5 weeks.

Samples of riboflavin, pyridoxine and thiamine were individually coated in a similar manner with stearic acid. Additional samples of these vitamins were individually coated with the monoand diglyceride mixture of the present invention. All samples were stored for a period of five weeks at room temperature.

At the end of the storage period, all samples were inspected and it was found that only the niacinamide coated with stearic acid has formed a hard mass which had to be physically broken into pieces with an iron bar before it could be blended or further processed.

By this experimental work, it can be seen that the novel process of the instant invention facilitates the production of a niacinamide powder equal in desirable characteristics to niacinamide coated with stearic acid according to the prior art and greatly improved in physical handling characteristics as evidenced by its freedom from caking during storage.

For a fuller understanding of the nature and objects of this invention, reference may be had to the following examples which are given merely as further illustrations of the invention and are not to be construed in a limiting sense. All parts given in the examples are parts by weight unless otherwise indicated.

EXAMPLE 1 In this example 59.0 parts of Atmos were charged into a suitable vessel and heated while stirring to a temperature of about 70 C. Thereafter, 40.0 parts of niacinamide were added to the molten glyceride mixture with stirring. The resulting mixture was stirred for an additional 30-minute period to insure uniform distribution of the niacinamide in the glyceride mixture. Thereafter, the mixture was transferred to a centrifugal atomizer rotating at a speed of 12,500 rpm, with the molten mixture being fed at a rate of 20 gallons per hour. The liquid droplets which were formed were allowed to fall freely through the tower. Air, cooled to a temperature of 20 C., was continuously blown through the spray tower to quickly chill the droplets to convert them to discrete, solid particles. All the particles were carried over in the effluent air stream and collected in two cyclone separators. The particles were accumulated in drums at the discharge end of the cyclone separator, collected and combined.

The collected particles were transferred to a drying oven, heated to a temperature of about 45 C. and maintained therein at that temperature for a period of about 14 days. At the end of that time, it was found that the particles were devoid of the characteristic disagreeable taste of niacinamide. The aged particles were than transferred to a twin shell blender and 1.0 part of silicic acid was added thereto. The mixture was blended until the particles were uniformly dusted with the silicic acid. The dusted product was then screened through a 30 mesh screen.

There was thus obtained a niacinamide-containing product in the form of palatable, free-flowing, nonagglomerating particles all of which particles passed through a 30 mesh screen, and up to about 50 percent by weight of which passed through a 200 mesh screen.

EXAMPLE 2 The procedure described in Example 1 was repeated using 34.0 parts of niacinamide, 65.0 parts of Atoms 150 and 1.0 part of silicic acid.

There was thus obtained a niacinamide-containing product in the form of a free-flowing powder which was completely palatable, free-flowing and nonagglomerating. The powder was made up of particles which passed through a 30 mesh screen, with up to about 50 percent by weight of such particles passing also through a 200 mesh screen.

EXAMPLE 3 The procedure described in Example 1 was repeated using, however, 25.0 parts of niacinamide, 74.0 parts of Atmos 150 and 1.0 part of silicic acid.

There was thus obtained a niacinamide-containing product in the form of palatable, free-flowing, nonagglomerating particles, all of which particles passed through a 30 mesh screen and up to about 50 percent by weight of which passed through a 200 mesh screen.

We claim:

1. ln a process of making a therapeutically active tasteless niacinamide powder which comprises atomizing a melt of niacinamide and a fatty acid substance into discrete liquid droplets; cooling said droplets into congealed beadlets; and aging said beadlets wherein the beadlets are dusted with silicic acid; the improvement which comprises stabilizing said niacinamide powder against caking during storage by using for said fatty acid substance a quantity of a mixture of monoglycerides and diglycerides of naturally occurring fatty acids having from 16 to 18 carbon atoms such that the weight of said mixture constitutes by weight of the total composition, from about 63.0 percent to about 67.0 percent and the niacinamide constitutes from about 32.0 percent to about 36.0 percent. 

2. The improved process according to claim 1 wherein said mixture of monoglycerides and diglycerides of naturally occurring fatty acids is a mixture consisting essentially of mono- and di-glycerides of stearic acid and palmitic acid containing not more than 0.01 percent by weigh of butylated hydroxy anisole, 0.01 percent by weight of butylated hydroxy toluene and 0.01 percent by weight of citric acid.
 3. The improved process according to claim 2 wherein the step of dusting said beadlets with silicic acid occurs either before or after said aging step. 